2-(pyridine-4-yl)-N-(quinuclidin-2-yl)thiazole-4-carboxide nicotinic acetylcholine receptor ligands

ABSTRACT

Compounds of formula I: 
                         
wherein A, D, Ar 1 , E and Ar 2  are as defined in the specification, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, especially in the treatment or prophylaxis of psychotic and intellectual impairment disorders.

RELATED APPLICATIONS

This is a division of U.S. application Ser. No. 11/325,787, filed Jan.5, 2006, granted as U.S. Pat. No. 7,214,688, which is a division of U.S.application Ser. No. 10/123,856, filed Apr. 15, 2002, granted as U.S.Pat. No. 7,001,914, which is a continuation of International ApplicationPCT/SE01/00329 filed Feb. 15, 2001, which designates the United Statesof America, which claims priority under the Paris Convention ofApplication No. 0000540-5 filed in Sweden on Feb. 18, 2000.

TECHNICAL FIELD

This invention relates to novel biarylcarboxamides orpharmaceutically-acceptable salts thereof, processes for preparing them,pharmaceutical compositions containing them and their use in therapy. Afurther object is to provide active compounds that are potent ligandsfor nicotinic acetylcholine receptors (nAChRs).

BACKGROUND OF THE INVENTION

The use of compounds which bind nicotinic acetylcholine receptors in thetreatment of a range of disorders involving reduced cholinergic functionsuch as Alzheimer's disease, cognitive or attention disorders, anxiety,depression, smoking cessation, neuroprotection, schizophrenia,analgesia, Tourette's syndrome, and Parkinson's disease has beendiscussed in McDonald et al. (1995) “Nicotinic Acetylcholine Receptors:Molecular Biology, Chemistry and Pharmacology”, Chapter 5 in AnnualReports in Medicinal Chemistry, vol. 30, pp. 41-50, Academic Press Inc.,San Diego, Calif.; and in Williams et al. (1994) “Neuronal NicotinicAcetylcholine Receptors,” Drug News & Perspectives, vol. 7, pp. 205-223.

DISCLOSURE OF THE INVENTION

According to the invention, it has been found that compounds of formulaI:

wherein:

A represents:

D represents oxygen or sulfur;

E represents a single bond, oxygen, sulfur, or NR¹⁰;

R represents hydrogen or methyl;

Ar¹ represents a 5- or 6-membered aromatic or heteroaromatic ringcontaining zero to three nitrogen atoms, zero or one oxygen atom, andzero or one sulfur atom;

Ar² represents a 5- or 6-membered aromatic or heteroaromatic ringcontaining zero to three nitrogen atoms, zero or one oxygen atom, andzero or one sulfur atom, or; an 8-, 9- or 10-membered fused aromatic orheteroaromatic ring system containing zero to three nitrogen atoms, zeroto one oxygen atom, and zero to one sulfur atom;

wherein when Ar² is unsubstituted phenyl, Ar¹ is not pyrazolyl; thearomatic rings Ar¹ and Ar² optionally substituted with one to threesubstituents selected from: halogen, C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, CN, NO₂, NR¹R², CH₂NR¹R², OR³, CH₂OR³, CO₂R⁴, and CF₃; butif Ar¹ is phenyl and Ar² is quinolynyl, then Ar² is substituted with 0,1, 2 or 3 substituents selected from C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, CN, NO₂, NR¹R², CH₂NR¹R², OR³, CH₂OR³ and CO₂R⁴;

R¹, R², and R³ are independently C₁₋₄alkyl, aryl, heteroaryl, C(O)R⁵,C(O)NHR⁶, C(O)R⁷, SO₂R⁸ or R¹ and R² may together be (CH₂)_(j)G(CH₂)_(k)where G is oxygen, sulfur, NR⁹, or a bond;

j is 2, 3 or 4;

k is 0, 1 or 2;

R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰, are independently C₁₋₄alkyl, aryl, orheteroaryl; or an enantiomer thereof, or pharmaceutically-acceptablesalts thereof, with the provisos that:

if D represents oxygen, E represents a single bond, and A represents:

and either Ar¹ or Ar² represents a pyrazole ring, then all optionalsubstituents on the pyrazole ring are hydrogen; and

if Ar¹ represents a pyridine ring, Ar² represents an aryl ring, and Arepresents:

then all optional substituents on the pyridine ring shall be hydrogen;and formula I does not represent:

are potent ligands for nicotinic acetylcholine receptors.

Unless otherwise indicated, the C₁₋₄alkyl groups referred to herein,e.g., methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl,s-butyl, whether alone or part of another group, may be straight-chainedor branched, and the C₃₋₄ alkyl groups may also be cyclic, e.g.,cyclopropyl, cyclobutyl. Alkyl groups referred to herein may optionallybe substituted with one to three halogen atoms.

Unless otherwise indicated, aryl refers to a phenyl ring which mayoptionally be substituted with one to three of the followingsubstituents selected from: halogen, C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, NR¹R², CH₂NR¹R², OR³, CH₂OR³, CO₂R⁴, CN, NO₂, and CF₃.

Unless otherwise indicated, heteroaryl refers to a 5- or 6-memberedaromatic or heteroaromatic ring containing zero to three nitrogen atoms,zero or one oxygen atom, and zero or one sulfur atom, provided that thering contains at least one nitrogen, oxygen, or sulfur atom, which mayoptionally be substituted with one or more substituents selected from:halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, NR¹R², CH₂NR¹R², OR³,CH₂OR³, CO₂R⁴, CN, NO₂, and CF₃.

Unless otherwise indicated, halogen refers to fluorine, chlorine,bromine, or iodine.

Pharmaceutically-acceptable derivatives include solvates and salts. Forexample, the compounds of formula I can form acid addition salts withacids, such as the conventional pharmaceutically-acceptable acids, forexample, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric,salicylic, citric, lactic, mandelic, tartaric and methanesulfonic acids.

Preferred compounds of the invention are compounds according to formulaI wherein A represents:

or an enantiomer thereof, and pharmaceutically-acceptable salts thereof.

Preferred embodiments of the invention include compounds of formula Iwherein D represents oxygen; or an enantiomer thereof, andpharmaceutically-acceptable salts thereof.

Preferred embodiments of the invention include compounds of formula Iwherein E represents a single bond; or an enantiomer thereof, andpharmaceutically-acceptable salts thereof.

Preferred embodiments of the invention include compounds of formula Iwherein E represents oxygen or NR¹⁰; or an enantiomer thereof, andpharmaceutically-acceptable salts thereof.

Preferred embodiments of the invention include compounds of formula Iwherein Ar¹ represents a 5- or 6-membered aromatic or heteroaromaticring containing zero or one nitrogen atom, zero or one oxygen atom, andzero or one sulfur atom; or an enantiomer thereof, andpharmaceutically-acceptable salts thereof. Among these, compounds inwhich Ar¹ represents a benzene ring, furan ring or thiophene ring, areparticularly preferred.

Preferred embodiments of the invention include compounds of formula Iwherein Ar² represents a 5- or 6-membered aromatic or heteroaromaticring containing zero to three nitrogen atoms, zero or one oxygen atom,and zero or one sulfur atom; or an enantiomer thereof, andpharmaceutically-acceptable salts thereof. Among these, compounds inwhich Ar² represents a benzene ring, furan ring, thiophene ring, orpyridine ring are particularly preferred.

Preferred embodiments of the invention include compounds of formula I,wherein the aromatic ring Ar¹ is substituted with −EAr² and thecarboxamide, or thiocarboxamide group, C(=D)NHA, but no furthersubstituents; or an enantiomer thereof, and pharmaceutically-acceptablesalts thereof.

Preferred embodiments of the invention include compounds in which the−EAr² and the carboxamide or thiocarboxamide group, C(=D)NHA,substituents on Ar¹ are positioned in a 1,3-relationship relative toeach other; or an enantiomer thereof, and pharmaceutically-acceptablesalts thereof.

Preferred embodiments of the invention include compounds of formula Iwherein Ar¹ or Ar² is substituted with zero or one substituents selectedfrom: halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, NO₂, NR¹R²,CH₂NR¹R², OR³, CH₂OR³, CO₂R⁴, and CF₃; or an enantiomer thereof, andpharmaceutically-acceptable salts thereof.

Particularly preferred embodiments of the invention also includecompounds of formula I wherein A represents:

D represents oxygen;

E represents a single bond;

Ar¹ represents a 5- or 6-membered aromatic or heteroaromatic ringcontaining zero or one nitrogen atom, zero or one oxygen atom, and zeroor one sulfur atom, and most preferably represents a benzene ring, furanring or thiophene ring;

Ar² represents a 5- or 6-membered aromatic or heteroaromatic ringcontaining zero to three nitrogen atoms, zero or one oxygen atom, andzero or one sulfur atom;

The aromatic ring Ar¹ is substituted with −EAr² and the carboxamidegroup, C(═O)NHA, but no further substituents, and these substituents onAr¹ are most preferably positioned in a 1,3-relationship relative toeach other;

Ar² is substituted with zero or one substituents selected from: halogen,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, NO₂, NR¹R², CH₂NR¹R², OR³,CH₂OR³, CO₂R⁴, and CF₃; or an enantiomer thereof, andpharmaceutically-acceptable salts thereof.

Particularly preferred embodiments of the invention include compounds offormula I wherein A represents:

D represents oxygen;

E represents oxygen, or NH;

Ar¹ represents a 5- or 6-membered aromatic or heteroaromatic ringcontaining zero or one nitrogen atom, zero or one oxygen atom, and zeroor one sulfur atom, and more preferably represents a benzene ring, furanring or thiophene ring;

Ar² represents a 5- or 6-membered aromatic or heteroaromatic ringcontaining zero to three nitrogen atoms, zero or one oxygen atom, andzero or one sulfur atom;

The aromatic ring Ar¹ is substituted with −EAr² and the carboxamidegroup, C(═O)NHA, but no further substituents, and these substituents onAr¹ are more preferably positioned in a 1,3-relationship relative toeach other;

Ar² is substituted with zero or one substituents selected from: halogen,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, NO₂, NR¹R², CH₂NR¹R², OR³,CH₂OR³, CO₂R⁴, and CF₃; or an enantiomer thereof, andpharmaceutically-acceptable salts thereof.

Preferred embodiments of the invention include compounds according toformula I wherein A represents:

and the configuration of the carbon atom in the quinuclidine to whichthe amide nitrogen is attached is (R), and pharmaceutically-acceptablesalts thereof.

Preferred compounds of the invention include the following:

-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylfuran-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-thienyl)benzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-phenylbenzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-pyridyl)benzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-methoxyphenyl)benzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(2-methoxyphenyl)benzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-(N-acetylamino)phenyl)benzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-fluorophenyl)benzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-methylphenyl)benzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(2-thienyl)benzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3,5-dichlorophenyl)benzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(2-naphthyl)benzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(4-fluorophenyl)benzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-thienyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-benzo[b]furanyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-thienyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-methoxyphenyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-fluorophenyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-naphthyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-methylphenyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-furyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-furyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-(2-pyridyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-(4-pyridyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-(3-pyridyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-nitrophenyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-trifluoromethylphenyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-ethoxyphenyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-3-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-chlorophenyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(2-(3-pyridyl)thiazole-4-carboxamide)-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(2-(4-pyridyl)thiazole-4-carboxamide)-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N,N-dimethylamino)phenyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(8-quinolinyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-3-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-phenylthiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-cyanophenyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-methylamino)phenyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-hydroxyphenyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridylamino)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(4-morpholinyl)phenyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(aminomethyl)phenyl)thiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenoxythiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N,N-dimethylamino)phenyl)furan-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-formylphenyl)thiophene-2-carboxamide);    and-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(hydroxymethyl)phenyl)thiophene-2-carboxamide).

Particularly preferred compounds of the invention include the following:

-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylfuran-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-thienyl)benzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-phenylbenzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-pyridyl)benzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-methoxyphenyl)benzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(2-methoxyphenyl)benzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-(N-acetylamino)phenyl)benzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-fluorophenyl)benzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-methylphenyl)benzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(2-thienyl)benzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3,5-dichlorophenyl)benzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(2-naphthyl)benzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(4-fluorophenyl)benzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-thienyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-benzo[b]furanyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-thienyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-methoxyphenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-fluorophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-naphthyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-methylphenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-furyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-furyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-(2-pyridyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-(4-pyridyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-(3-pyridyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-nitrophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-trifluoromethylphenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-ethoxyphenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-3-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)[5-(4-chlorophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(2-(3-pyridyl)thiazole-4-carboxamide)-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(2-(4-pyridyl)thiazole-4-carboxamide)-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N,N-dimethylamino)phenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(8-quinolinyl)thiophene-2-carboxamide);-   (S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-2-carboxamide);-   (S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiophene-2-carboxamide);-   (S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide);-   (S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-3-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-phenylthiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-cyanophenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-methylamino)phenyl)thiophene-2-carboxamide);-   (R)-N-(1-Aza-bicyclo[2.2.2]oct-3-yl)(5-(3-hydroxyphenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridylamino)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)thiophene-2-carboxamide);-   (R)-N-(1-Aza-bicyclo[2.2.2]oct-3-yl)(5-(3-(4-morpholinyl)phenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(aminomethyl)phenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenoxythiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N,N-dimethylamino)phenyl)furan-2-carboxamide);-   (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(3-formylphenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(hydroxymethyl)phenyl)thiophene-2-carboxamide);

and pharmaceutically-acceptable salts thereof.

Among these compounds, the following compounds of the invention are moreparticularly preferred:

-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylfuran-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-thienyl)benzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-phenylbenzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-(N-acetylamino)phenyl)benzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(2-thienyl)benzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-thienyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-benzo[b]furanyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-thienyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-fluorophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-naphthyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-methylphenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-furyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-(2-pyridyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-nitrophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-trifluoromethylphenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-ethoxyphenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-3-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)[5-(4-chlorophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N,N-dimethylamino)phenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(8-quinolinyl)thiophene-2-carboxamide);-   (S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-2-carboxamide);-   (S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiophene-2-carboxamide);-   (S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide);-   (S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-3-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-phenylthiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-cyanophenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-methylamino)phenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-hydroxyphenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridylamino)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(4-morpholinyl)phenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(aminomethyl)phenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenoxythiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N,N-dimethylamino)phenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(hydroxymethyl)phenyl)thiophene-2-carboxamide);

and pharmaceutically-acceptable salts thereof.

Among these compounds, the following compounds of the invention are mostparticularly preferred:

-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-fluorophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-nitrophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-trifluoromethylphenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-3-carboxamide);-   (S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-2-carboxamide);-   (S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-phenylthiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-cyanophenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-hydroxyphenyl)thiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenoxythiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)furan-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(hydroxymethyl)phenyl)thiophene-2-carboxamide);

and pharmaceutically-acceptable salts thereof.

Methods of Preparation

In the reaction schemes and text that follow, A, E, Ar¹, and Ar² unlessotherwise indicated, are as defined above for formula I.

The compounds of formula I in which E represent a single bond may beprepared according to the following methods outlined in Scheme 1.

Compounds of formula I wherein D represents oxygen and E represents asingle bond may be prepared from compounds of formula VI wherein Jrepresents a halogen or OSO₂CF₃ substituent at the position of ring Ar¹at which the bond to ring Ar² is formed, by reaction with an appropriateorganometallic compound of formula VII in the presence of a suitableorganometallic catalyst and solvent. Suitable compounds of formula VIIinclude boronic acids, in which M represents B(OH)₂ and organotincompounds, in which M represents a suitable trialkylstannyl group, forexample trimethylstannyl or tri-n-butylstannyl. Suitable organometalliccatalysts include palladium(0) complexes, for exampletetrakis(triphenylphosphine)palladium(0) or a combination oftris(dibenzylideneacetone)dipalladium(0) and a suitable triarylphosphineor triarylarsine ligand, for example triphenylphosphine,tri(o-tolyl)phosphine or triphenylarsine. Suitable solvents includeinert ether solvents, for example 1,2-dimethoxyethane, tetrahydrofuran,or 1,4-dioxane, or alcohols, such as ethanol, or mixtures thereof. Ifthe compound of formula VII is a boronic acid, the presence of asuitable base in addition to the other reagents is preferred. Suitablebases include sodium carbonate, cesium carbonate, and barium hydroxide.The reaction is carried out at a temperature of 0-120° C., andpreferably at a temperature of 60-120° C.

Compounds of formula I wherein D represents oxygen and E represents asingle bond may also be prepared from organometallic compounds offormula VIII by reaction with a compound of formula IX in which Jrepresents a halogen or OSO₂CF₃ in the presence of a suitableorganometallic catalyst and solvent. Suitable compounds of formula VIIIinclude boronic acids, in which M represents B(OH)₂ and organotincompounds, in which M represents a suitable trialkylstannyl group, forexample trimethylstannyl or tri-n-butylstannyl. Suitable organometalliccatalysts include palladium(0) complexes, for exampletetrakis(triphenylphosphine)palladium(0) or a combination oftris(dibenzylideneacetone)dipalladium(0) and a suitable triarylphosphineor triarylarsine ligand, for example triphenylphosphine,tri(o-tolyl)phosphine or triphenylarsine. Suitable solvents includeinert ether solvents, for example 1,2-dimethoxyethane, tetrahydrofuran,or 1,4-dioxane, or alcohols, such as ethanol, or mixtures thereof. Ifthe compound of formula VIII is a boronic acid, the presence of asuitable base in addition to the other reagents is preferred. Suitablebases include sodium carbonate, cesium carbonate, and barium hydroxide.The reaction is carried out at a temperature of 0-120° C., andpreferably at a temperature of 60-120° C.

Compounds of formula I wherein D represents oxygen and E represents asingle bond may also be prepared from compounds of formula X by reactionwith a suitable compound of formula XI, wherein L represents a suitableleaving group, using a suitable acylation procedure. Suitable leavinggroups L include: OH, halogen, OAlkyl, OAryl, OCOAlkyl, OCOAryl. Asuitable acylation procedure involves treatment of a compound of formulaX with a compound of formula XI at 0-120° C. in a suitable solvent. Thepresence of a base, or, when Y═OH, a coupling agent, may also benecessary for the reaction to occur. Suitable bases for the reactioninclude: 4-(N,N-dimethylamino)pyridine, pyridine, triethylamine,N,N-diisopropylethylamine. The preferred base isN,N-diisopropylethylamine. Suitable coupling agents when L=OH include:carbodiimides, for example 1,3-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride; phosphoniumreagents, for example benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate or benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate; and uronium reagents, for exampleO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate. Thepreferred coupling agent isO-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate.Suitable solvents for the reaction include N,N-dimethylformamide,dimethylsulfoxide, tetrahydrofuran, or chloroform. The preferred solventis N,N-dimethylformamide. The reaction is preferably performed at atemperature of 0-50° C., and most preferably at a temperature of 20-30°C.

Compounds of formula I in which D represents sulfur and E represents asingle bond may be prepared from compounds of formula I in which Drepresents oxygen and E represents a single bond by reaction with asuitable sulfide in a suitable solvent. The preferred sulfides arephosphorus sulfides, in particular 4-methoxyphenylthionophosphinesulfide dimer (“Lawesson's Reagent”), and diphosphorus pentasulfide.Suitable solvents for the reaction include aryl hydrocarbon solvents,for example toluene or xylene. The reaction is performed at atemperature of 0-200° C., and preferably at a temperature of 50-180° C.

Certain compounds of formula VI wherein J represents halogen may beprepared from compounds of formula VI wherein J represents hydrogen byreaction with a suitable halogenating agent in a suitable solvent.Suitable halogenating agents include bromine. Suitable solvents includeacetic acid. The reaction is preferably performed at a temperature of0-50° C., and most preferably at a temperature of 0-25° C.

Compounds of formula VI wherein J represents OSO₂CF₃ may be preparedfrom compounds of formula VI wherein J represents OH by reaction withtrifluoromethanesulfonic anhydride or othertrifluoromethanesulfonylating agent in the presence of a base and asuitable solvent. Suitable bases include pyridine, and2,6-di-t-butylpyridine. The reaction is preferably performed at atemperature of −78 to 120° C., and most preferably at a temperature of−78 to 0° C.

Compounds of formula VI wherein J represents hydrogen, halogen, OH, orOSO₂CF₃ may be prepared from compounds of formula X by reaction with asuitable compound of formula XII, wherein L represents a suitableleaving group and J represents hydrogen, halogen, OH, or OSO₂CF₃, usinga suitable acylation procedure. Suitable leaving groups L include: OH,halogen, OAlkyl, OAryl, OCOAlkyl, OCOAryl. A suitable acylationprocedure involves treatment of a compound of formula X with a compoundof formula XII at 0-120° C. in a suitable solvent. The presence of abase, or, when L=OH, a coupling agent, may also be necessary for thereaction to occur. Suitable bases for the reaction include:4-(N,N-dimethylamino)pyridine, pyridine, triethylamine,N,N-diisopropylethylamine. The preferred base isN,N-diisopropylethylamine. Suitable coupling agents when Y═OH include:carbodiimides, for example 1,3-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride; phosphoniumreagents, for example benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate or benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate; and uronium reagents, for exampleO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate. Thepreferred coupling agent isO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate.Suitable solvents for the reaction include N,N-dimethylformamide,dimethylsulfoxide, tetrahydrofuran, or chloroform. The preferred solventis N,N-dimethylformamide. The reaction is preferably performed at atemperature of 0-50° C., and most preferably at a temperature of 20-30°C.

Compounds of formula VIII in which M represents B(OH)₂ may be preparedfrom compounds of formula VI in which J represents hydrogen, halogen, orOSO₂CF₃ by methods known to one skilled in the art. For examplecompounds of formula VI in which J represents hydrogen or halogen may beconverted to compounds of formula VIII in which M represents B(OH)₂ viaconversion to the corresponding aryllithium or arylmagnesium compoundsfollowed by reaction with trimethylborate and subsequent hydrolysis ofthe resulting borate ester. The reaction is performed in a suitableinert solvent, for example, tetrahydrofuran. Alternatively, compounds offormula VI wherein J represents halogen or OSO₂CF₃ may be converted tocompounds of formula VIII in which M represents B(OH)₂ via reaction withbis(pinacolato)diboron and an organometallic catalyst, followed byhydrolysis of the resulting borate ester. For typical procedures foreffecting such conversions, see, for example, Organic Syntheses, 1963,Coll. Vol. 4, 68; J. Org. Chem. 1995, 60, 7508.

Compounds of formula VIII in which M represents a trialkylstannyl groupmay be prepared from compounds of formula VI in which J representshydrogen, halogen, or OSO₂CF₃ by methods known to one skilled in theart. For example compounds of formula VI in which J represents hydrogenor halogen may be converted to compounds of formula VIII in which Mrepresents a trialkylstannyl group via conversion to the correspondingaryllithium or arylmagnesium compounds followed by reaction with anappropriate trialkylstannyl halide. The reaction is performed in asuitable inert solvent, for example, tetrahydrofuran. The reaction isperformed at a temperature of −78° C. to 20° C., preferably at −78° C.to 0° C. Alternatively, compounds of formula VI wherein J representshalogen or OSO₂CF₃ may be converted to compounds of formula VIII inwhich M represents a trialkylstannyl group via reaction with theappropriate bis(trialkyltin). The reaction is performed in a suitableinert solvent, for example tetrahydrofuran, in the presence of asuitable organometallic catalyst, for exampletetrakis(triphenylphosphine). The reaction is performed at a temperatureof 0° C. to 150° C., preferably at 20° C. to 100° C.

Compounds of formula VIII wherein M represents B(OH)₂ or atrialkylstannyl group may be prepared from compounds of formula X byreaction with a suitable compound of formula XIII, wherein L representsa suitable leaving group M represents B(OH)₂ or a trialkylstannyl group,using a suitable acylation procedure. Suitable leaving groups L include:OH, halogen, OAlkyl, OAryl, OCOAlkyl, OCOAryl. A suitable acylationprocedure involves treatment of a compound of formula X with a compoundof formula XIII at 0-120° C. in a suitable solvent. The presence of abase, or, when L=OH, a coupling agent, may also be necessary for thereaction to occur. Suitable bases for the reaction include:4-(N,N-dimethylamino)pyridine, pyridine, triethylamine,N,N-diisopropylethylamine. The preferred base isN,N-diisopropylethylamine. Suitable coupling agents when L=OH include:carbodiimides, for example 1,3-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride; phosphoniumreagents, for example benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate or benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate; and uronium reagents, for exampleO-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate. Thepreferred coupling agent isO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate.Suitable solvents for the reaction include N,N-dimethylformamide,dimethylsulfoxide, tetrahydrofuran, or chloroform. The preferred solventis N,N-dimethylformamide. The reaction is preferably performed at atemperature of 0-50° C., and most preferably at a temperature of 20-30°C.

Compounds of formula XI may be prepared from compounds of formula XIIwherein J represents a halogen or OSO₂CF₃ substituent at the position ofring Ar¹ at which the bond to ring Ar² is formed, by reaction with anappropriate organometallic compound of formula VII in the presence of asuitable organometallic catalyst and solvent. Suitable compounds offormula VII include boronic acids, in which M represents B(OH)₂ andorganotin compounds, in which M represents a suitable trialkylstannylgroup, for example trimethylstannyl or tri-n-butylstannyl. Suitableorganometallic catalysts include palladium(0) complexes, for exampletetrakis(triphenylphosphine)palladium(0) or a combination oftris(dibenzylidieneacetone)dipalladium(0) and a suitabletriarylphosphine or triarylarsine ligand, for exampletriphenylphosphine, tri(o-tolyl)phosphine or triphenylarsine. Suitablesolvents include inert ether solvents, for example 1,2-dimethoxyethane,tetrahydrofuran, or 1,4-dioxane, or alcohols, such as ethanol, ormixtures thereof. If the compound of formula VII is a boronic acid, thepresence of a suitable base in addition to the other reagents ispreferred. Suitable bases include sodium carbonate, cesium carbonate,and barium hydroxide. The reaction is carried out at a temperature of0-120° C., and preferably at a temperature of 60-120° C.

Compounds of formula XI may also be prepared from organometalliccompounds of formula XIII by reaction with a compound of formula IX inwhich J represents a halogen or OSO₂CF₃ in the presence of a suitableorganometallic catalyst and solvent. Suitable compounds of formula XIIIinclude boronic acids, in which M represents B(OH)₂ and organotincompounds, in which M represents a suitable trialkylstannyl group, forexample trimethylstannyl or tri-n-butylstannyl. Suitable organometalliccatalysts include palladium(0) complexes, for exampletetrakis(triphenylphosphine)palladium(0) or a combination oftris(dibenzylideneacetone)dipalladium(0) and a suitable triarylphosphineor triarylarsine ligand, for example triphenylphosphine,tri(o-tolyl)phosphine or triphenylarsine. Suitable solvents includeinert ether solvents, for example 1,2-dimethoxyethane, tetrahydrofuran,or 1,4-dioxane, or alcohols, such as ethanol, or mixtures thereof. Ifthe compound of formula VIII is a boronic acid, the presence of asuitable base in addition to the other reagents is preferred. Suitablebases include sodium carbonate, cesium carbonate, and barium hydroxide.The reaction is carried out at a temperature of 0-120° C., andpreferably at a temperature of 60-120° C.

Compounds of formula VII and compounds of formula XIII are eithercommercially available, or may be prepared by methods known to oneskilled in the art. In particular, methods are known to one skilled inthe art for the conversion of aryl halides or heteroaryl halides to arylor heteroaryl boronic acids or aryl or heteroaryl trialkylstannanes,providing methods for the conversion of compounds of formula IX in whichJ represents halogen to compounds of formula VII and compounds offormula XII in which J represents halogen to compounds of formula XIII.For example, boronic acids may be synthesised from aryl or heteroarylhalides via conversion to the aryllithium or arylmagnesium compoundsfollowed by reaction with trimethylborate, or via reaction withbis(pinacolato)diboron and an organometallic catalyst, followed byhydrolysis of the resulting borate ester (see, for example, OrganicSyntheses, 1963, Coll. Vol. 4, 68; J. Org. Chem. 1995, 60, 7508).Trialkylstannanes may be synthesised from aryl or heteroaryl halides viaconversion to the aryllithium or arylmagnesium compounds followed byreaction with the appropriate chlorotrialkyltin, or via reaction withthe appropriate bis(trialkyltin) and an organometallic catalyst.

The compounds of formula I in which E represents oxygen, sulfur, or NR¹⁰may be prepared according to the following methods outlined in Scheme 2.

Compounds of formula I wherein D represents oxygen and E represents NR¹⁰may be prepared from compounds of formula VI wherein J represents ahalogen or OSO₂CF₃ substituent at the position of ring Ar¹ at which thebond to nitrogen is formed, by reaction with an appropriate amine offormula XIV in which EH represents NHR¹⁰. The reaction may be performedby heating in an inert solvent in the presence of a suitable strongbase. Suitable inert solvents include ether solvents, for exampletetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, ordi(2-methoxyethyl)ether, a hydrocarbon solvent, for example benzene ortoluene, or an amide solvent, for example dimethylformamide, orN-methyl-2-pyrrolidinone. The preferred solvent is tetrahydrofuran.Suitable strong bases include alkali metal alkoxide or amide bases, forexample sodium t-butoxide or potassium t-butoxide, lithiumbis(trimethylsilyl)amide, or lithium diisopropylamide. The preferredstrong base is sodium t-butoxide. The reaction may require, and ispreferably performed in, the presence of an organometallic catalyst.Suitable organometallic catalysts include complexes of palladium(0) witha suitable phosphine ligand, preferably a triarylphosphine ligand, andmost preferably a bidentate triarylphosphine ligand. Preferred ligandsinclude 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl or1,1′-bis(diphenylphosphino)ferrocene. The catalyst may be synthesised bythe combination of a suitable source of palladium(0), for exampletris(dibenzylideneacetone)dipalladium(0), with the phosphine ligand, andmay either be pre-formed or formed in situ by including the palladiumsource and phophine ligand in the reaction mixture. The reaction iscarried out at a temperature of 0-150° C., and preferably at atemperature of 60-120° C.

Compounds of formula I wherein D represents oxygen and E represents NR¹⁰may also be prepared from compounds of formula IX wherein J represents ahalogen or OSO₂CF₃ substituent at the position of ring Ar² at which thebond to nitrogen is formed, by reaction with an appropriate amine offormula XV in which EH represents NHR¹⁰. The reaction may be performedby heating in an inert solvent in the presence of a suitable strongbase. Suitable inert solvents include ether solvents, for exampletetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, ordi(2-methoxyethyl)ether, a hydrocarbon solvent, for example benzene ortoluene, or an amide solvent, for example dimethylformamide, orN-methyl-2-pyrrolidinone. The preferred solvent is tetrahydrofuran.Suitable strong bases include alkali metal alkoxide or amide bases, forexample sodium t-butoxide or potassium t-butoxide, lithiumbis(trimethylsilyl)amide, or lithium diisopropylamide. The preferredstrong base is sodium t-butoxide. The reaction may require, and ispreferably performed in, the presence of an organometallic catalyst.Suitable organometallic catalysts include complexes of palladium(0) witha suitable phosphine ligand, preferably a triarylphosphine ligand, andmost preferably a bidentate triarylphosphine ligand. Preferred ligandsinclude 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl or1,1′-bis(diphenylphosphino)ferrocene. The catalyst may be synthesised bythe combination of a suitable source of palladium(0), for exampletris(dibenzylideneacetone)dipalladium(0), with the phosphine ligand, andmay either be pre-formed or formed in situ by including the palladiumsource and phophine ligand in the reaction mixture. The reaction iscarried out at a temperature of 0-150° C., and preferably at atemperature of 60-120° C.

Compounds of formula I wherein D represents oxygen and E representsoxygen or sulfur may be prepared from compounds of formula VI wherein Jrepresents a halogen or OSO₂CF₃ substituent at the position of ring Ar¹at which the bond to oxygen is formed, by reaction with an appropriatecompound of formula XIV in which EH represents OH or SH. The reactionmay be performed by heating in an inert solvent in the presence of asuitable base. The reaction may require, and is preferably performed in,the presence of a catalyst. Suitable inert solvents include ethersolvents, for example tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,or di(2-methoxyethyl)ether, an amide solvent, for exampledimethylformamide, or N-methyl-2-pyrrolidinone, or a basic heterocyclicaromatic solvent, for example pyridine. The preferred solvent ispyridine. Suitable bases include alkali metal alkoxides, or alkali metalcarbonates, for example potassium carbonate. Suitable organometalliccatalysts include copper or its salts, preferably copper(I) salts, andmost preferably copper(I) iodide. The reaction is carried out at atemperature of 0-150° C., and preferably at a temperature of 100-150° C.

Compounds of formula I wherein D represents oxygen and E representsoxygen or sulfur may also be prepared from compounds of formula IXwherein J represents a halogen or OSO₂CF₃ substituent at the position ofring Ar² at which the bond to nitrogen is formed, by reaction with anappropriate compound of formula XV in which EH represents OH or SH. Thereaction may be performed by heating in an inert solvent in the presenceof a suitable base. The reaction may require, and is preferablyperformed in, the presence of a catalyst. Suitable inert solventsinclude ether solvents, for example tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, or di(2-methoxyethyl)ether, an amide solvent, forexample N,N-dimethylformamide, or N-methylpyrrolidinone, or a basicheterocyclic aromatic solvent, for example pyridine. The preferredsolvent is pyridine. Suitable bases include alkali metal alkoxides, oralkali metal carbonates, for example potassium carbonate. Suitableorganometallic catalysts include copper or its salts, preferablycopper(I) salts, and most preferably copper(I) iodide. The reaction iscarried out at a temperature of 0-150° C., and preferably at atemperature of 100-150° C.

Compounds of formula I wherein D represents oxygen and E representsoxygen, sulfur, or NR¹⁰ may also be prepared from compounds of formula Xby reaction with a suitable compound of formula XVI, wherein Erepresents oxygen, sulfur, or NR¹⁰ and L represents a suitable leavinggroup, using a suitable acylation procedure. Suitable leaving groups Linclude: OH, halogen, OAlkyl, OAryl, OCOAlkyl, OCOAryl. A suitableacylation procedure involves treatment of a compound of formula X with acompound of formula XI at 0-120° C. in a suitable solvent. The presenceof a base, or, when Y═OH, a coupling agent, may also be necessary forthe reaction to occur. Suitable bases for the reaction include:4-(N,N-dimethylamino)pyridine, pyridine, triethylamine,N,N-diisopropylethylamine. The preferred base isN,N-diisopropylethylamine. Suitable coupling agents when L=OH include:carbodiimides, for example 1,3-dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride; phosphoniumreagents, for example benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate or benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate; and uronium reagents, for exampleO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate. Thepreferred coupling agent isO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate.Suitable solvents for the reaction include N,N-dimethylformamide,dimethylsulfoxide, tetrahydrofuran, or chloroform. The preferred solventis N,N-dimethylformamide. The reaction is preferably performed at atemperature of 0-50° C., and most preferably at a temperature of 20-30°C.

Compounds of formula XV wherein EH represents OH, SH, or NHR¹⁰ may beprepared from compounds of formula X by reaction with a suitablecompound of formula XVII, wherein L represents a suitable leaving groupand EH represents OH, SH or NHR¹⁰, using a suitable acylation procedure.Suitable leaving groups L include: OH, halogen, OAlkyl, OAryl, OCOAlkyl,OCOAryl. A suitable acylation procedure involves treatment of a compoundof formula X with a compound of formula XVII at 0-120° C. in a suitablesolvent. The presence of a base, or, when L=OH, a coupling agent, mayalso be necessary for the reaction to occur. Suitable bases for thereaction include: 4-(N,N-dimethylamino)pyridine, pyridine,triethylamine, N,N-diisopropylethylamine. The preferred base isN,N-diisopropylethylamine. Suitable coupling agents when L=OH include:carbodiimides, for example 1,3-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride; phosphoniumreagents, for example benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate or benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate; and uronium reagents, for exampleO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate. Thepreferred coupling agent isO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate.Suitable solvents for the reaction include N,N-dimethylformamide,dimethylsulfoxide, tetrahydrofuran, or chloroform. The preferred solventis N,N-dimethylformamide. The reaction is preferably performed at atemperature of 0-50° C., and most preferably at a temperature of 20-30°C.

Compounds of formula I, XIV, XV or XVII in which E represents NR¹⁰ andR¹⁰ represents an alkyl group may be prepared from compounds of thecorresponding formula wherein R¹⁰ represents hydrogen by a suitablealkylation procedure. Typical alkylation procedures include treatmentwith an appropriate alkyl halide or sulfonate ester and base, forexample sodium hydride, in a suitable solvent, for exampleN,N-dimethylformamide, or reductive alkylation using the appropriatealdehyde or ketone together with a suitable reducing agent in thepresence of an acidic catalyst and in an inert solvent. The preferredmethod is reductive alkylation. Suitable reducing agents include sodiumborohydride and sodium cyanoborohydride. The preferred reducing agent issodium borohydride. Suitable inert solvents include water, methanol orethanol. The preferred solvent is methanol. Suitable acidic catalystsinclude acetic acid or zinc chloride. The preferred acidic catalyst isacetic acid. The reaction is usually conducted at a temperature of0-100° C., and preferably at 20-65° C.

Compounds of formula I, XIV, XV or XVII in which E represents NR¹⁰ andR¹⁰ represents an aryl or heteroaryl group may be prepared fromcompounds of the corresponding formula wherein R¹⁰ represents hydrogenby reaction with an appropriate aromatic or heteroaromatic halide ortrifluoromethanesulfonate. The reaction may be performed by heating inan inert solvent in the presence of a suitable strong base. Suitableinert solvents include ether solvents, for example tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, or di(2-methoxyethyl)ether, ahydrocarbon solvent, for example benzene or toluene, or an amidesolvent, for example N,N-dimethylformamide, or N-methyl-2-pyrrolidinone.The preferred solvent is tetrahydrofuran. Suitable strong bases includealkali metal alkoxide or amide bases, for example sodium t-butoxide orpotassium t-butoxide, lithium bis(trimethylsilyl)amide, or lithiumdiisopropylamide. The preferred strong base is sodium t-butoxide. Thereaction may require, and is preferably performed in, the presence of anorganometallic catalyst. Suitable organometallic catalysts includecomplexes of palladium(0) with a suitable phosphine ligand, preferably atriarylphosphine ligand, and most preferably a bidentatetriarylphosphine ligand. Preferred ligands include2,2′bis(diphenylphosphino)-1,1′-binaphthyl or1,1′-bis(diphenylphosphino)ferrocene. The catalyst may be synthesised bythe combination of a suitable source of palladium(0), for exampletris(dibenzylidieneacetone)dipalladium(0), with the phosphine ligand,and may either be preformed or formed in situ by including the palladiumsource and phophine ligand in the reaction mixture. The reaction iscarried out at a temperature of 0-150° C., and preferably at atemperature of 60-120° C.

Compounds of formula I in which D represents sulfur and E representsoxygen or NR¹⁰ may be prepared from compounds of formula I in which Drepresents oxygen and E represents oxygen, or NR¹⁰ by reaction with asuitable sulfide in a suitable solvent. The preferred sulfides arephosphorus sulfides, in particular 4-methoxyphenylthionophosphinesulfide dimer (“Lawesson's Reagent”), and diphosphorus pentasulfide.Suitable solvents for the reaction include aryl hydrocarbon solvents,for example toluene or xylene. The reaction is performed at atemperature of 0-200° C., and preferably at a temperature of 50-180° C.

Compounds of formula XVI wherein D represents oxygen and E representsNR¹⁰ may be prepared from compounds of formula XII wherein J representsa halogen or OSO₂CF₃ substituent at the position of ring Ar¹ at whichthe bond to nitrogen is formed, by reaction with an appropriate amine offormula XIV in which EH represents NHR¹⁰, or, alternatively, fromcompounds of formula XVII in which EH represents NHR¹⁰ by reaction withan appropriate compound of formula IX wherein J represents a halogen orOSO₂CF₃ substituent at the position of ring Ar² at which the bond tonitrogen is formed. The reaction may be performed by heating in an inertsolvent in the presence of a suitable strong base. Suitable inertsolvents include ether solvents, for example tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, or di(2-methoxyethyl)ether, ahydrocarbon solvent, for example benzene or toluene, or an amidesolvent, for example N,N-dimethylformamide, or N-methyl-2-pyrrolidinone.The preferred solvent is tetrahydrofuran. Suitable strong bases includealkali metal alkoxide or amide bases, for example sodium t-butoxide orpotassium t-butoxide, lithium bis(trimethylsilyl)amide, or lithiumdiisopropylamide. The preferred strong base is sodium t-butoxide. Thereaction may require, and is preferably performed in, the presence of anorganometallic catalyst. Suitable organometallic catalysts includecomplexes of palladium (0) with a suitable phosphine ligand, preferablya triarylphosphine ligand, and most preferably a bidentatetriarylphosphine ligand. Preferred ligands include2,2′-bis(diphenylphosphino)-1,1′-binaphthyl or1,1′-bis(diphenylphosphino)ferrocene. The catalyst may be synthesised bythe combination of a suitable source of palladium(0), for exampletris(dibenzylideneacetone)dipalladium(0), with the phosphine ligand, andmay either be pre-formed or formed in situ by including the palladiumsource and phophine ligand in the reaction mixture. The reaction iscarried out at a temperature of 0-150° C., and preferably at atemperature of 60-120° C.

Compounds of formula XVI wherein D represents oxygen and E representsoxygen or sulfur may be prepared from compounds of formula XII wherein Jrepresents a halogen or OSO₂CF₃ substituent at the position of ring Ar¹at which the bond to oxygen or sulfur is formed, by reaction with anappropriate compound of formula XIV in which EH represents OH or SH, or,alternatively, from compounds of formula XVII in which EH represents OHor SH by reaction with an appropriate compound of formula IX wherein Jrepresents a halogen or OSO₂CF₃ substituent at the position of ring Ar²at which the bond to oxygen or sulfur is formed. The reaction may beperformed by heating in an inert solvent in the presence of a suitablebase. The reaction may require, and is preferably performed in, thepresence of a catalyst. Suitable inert solvents include ether solvents,for example tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, ordi(2-methoxyethyl)ether, an amide solvent, for exampleN,N-dimethylformamide, or N-methyl-2-pyrrolidinone, or a basicheterocyclic aromatic solvent, for example pyridine. The preferredsolvent is pyridine. Suitable bases include alkali metal alkoxides, oralkali metal carbonates, for example potassium carbonate. Suitableorganometallic catalysts include copper or its salts, preferablycopper(I) salts, and most preferably copper(I) iodide. The reaction iscarried out at a temperature of 0-150° C., and preferably at atemperature of 100-150° C.

Compounds of formula IX, X, and XII, XIV, and XVII are eithercommercially available, known in the literature, or may be prepared bymethods known to one skilled in the art.

It will be appreciated by one skilled in the art that certain optionalaromatic substituents in the compounds of the invention may beintroduced by employing aromatic substitution reactions, or functionalgroup transformations to modify an existing substituent, or acombination thereof. Such reactions may be effected either prior to orimmediately following the processes mentioned above, and are included aspart of the process aspect of the invention. The reagents and reactionconditions for such procedures are known in the art. Specific examplesof procedures which may be employed include, but are not limited to,electrophilic functionalisation of an aromatic ring, for example vianitration, halogenation, or acylation; transformation of a nitro groupto an amino group, for example via reduction, such as by catalytichydrogenation; acylation, alkylation, sulfonylation of an amino orhydroxyl group; replacement of an amino group by another functionalgroup via conversion to an intermediate diazonium salt followed bynucleophilic or free radical substitution of the diazonium salt; orreplacement of a halogen by another functional group, for example vianucleophilic or organometallically-catalysed substitution reactions.

Where necessary, hydroxy, amino, or other reactive groups may beprotected using a protecting group as described in the standard text“Protecting groups in Organic Synthesis”, 3^(rd) Edition (1999) byGreene and Wuts.

The above described reactions, unless otherwise noted, are usuallyconducted at a pressure of about one to about three atmospheres,preferably at ambient pressure (about one atmosphere).

Unless otherwise stated, the above described reactions are conductedunder an inert atmosphere, preferably under a nitrogen atmosphere.

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures by standard techniques.

Acid addition salts of the compounds of formula I which may be mentionedinclude salts of mineral acids, for example the hydrochloride andhydrobromide salts; and salts formed with organic acids such as formate,acetate, maleate, benzoate, tartrate, and fumarate salts.

Acid addition salts of compounds of formula I may be formed by reactingthe free base or a salt, enantiomer or protected derivative thereof,with one or more equivalents of the appropriate acid. The reaction maybe carried out in a solvent or medium in which the salt is insoluble orin a solvent in which the salt is soluble, e.g., water, dioxane,ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents,which may be removed in vacuum or by freeze drying. The reaction may bea metathetical process or it may be carried out on an ion exchangeresin.

The compounds of formula I exist in tautomeric or enantiomeric forms,all of which are included within the scope of the invention. The variousoptical isomers may be isolated by separation of a racemic mixture ofthe compounds using conventional techniques, e.g. fractionalcrystallisation, or chiral HPLC. Alternatively the individualenantiomers may be made by reaction of the appropriate optically activestarting materials under reaction conditions which will not causeracemisation.

Intermediates

A further aspect of the invention relates to intermediates. Of interestamong the intermediates are compounds of formula VI in Scheme 1. Theseintermediates are useful in the synthesis of compounds of formula I, buttheir use is not limited to the synthesis of such compounds. Forexample, compounds of formula VI are active as ligands for acetylcholinereceptors, and therefore share the utilities described for compounds offormula I.

Accordingly, there is also provided a compound of formula VI:

wherein:

Ar¹ represents a benzene, furan, or thiophene ring;

J represents halogen, or OSO₂CF₃, provided that when Ar¹ represents abenzene ring, J may only represent bromine, iodine, or OSO₂CF₃ in aposition meta or para to the carboxamide group; or an enantiomer thereofand pharmaceutically-acceptable salts thereof.

Preferred compounds of this aspect of the invention include thefollowing:

-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-bromobenzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-iodobenzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-iodobenzamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-bromothiophene-2-carboxamide);-   N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-3-carboxamide);

or an enantiomer thereof, and pharmaceutically-acceptable salts thereof.

Particularly preferred compounds of this aspect of the invention includethe following:

-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide);-   (S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-bromobenzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-iodobenzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-iodobenzamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-bromothiophene-2-carboxamide);-   (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-3-carboxamide);

or an enantiomer thereof, and pharmaceutically-acceptable salts thereof.

Intermediate compounds also exist in enantiomeric forms and may be usedas purified enantiomers, racemates or mixtures.

Pharmaceutical Compositions

A further aspect of the invention relates to a pharmaceuticalcomposition for treating or preventing a condition or disorder asexemplified below arising from dysfunction of nicotinic acetylcholinereceptor neurotransmission in a mammal, preferably a human, comprisingan amount of a compound of formula I, an enantiomer thereof or apharmaceutically-acceptable salt thereof, effective in treating orpreventing such disorder or condition in admixture with an inertpharmaceutically-acceptable diluent or carrier.

For the above-mentioned uses the dosage administered will, of course,vary with the compound employed, the mode of administration and thetreatment desired. However, in general, satisfactory results areobtained when the compounds of the invention are administered at a dailydosage of from about 0.1 mg to about 20 mg per kg of animal body weight,preferably given in divided doses 1 to 4 times a day or in sustainedrelease form. For man, the total daily dose is in the range of from 5 mgto 1,400 mg, more preferably from 10 mg to 100 mg, and unit dosage formssuitable for oral administration comprise from 2 mg to 1,400 mg of thecompound admixed with a solid or liquid pharmaceutical carrier ordiluent.

The compounds of formula I, or an enantiomer thereof, andpharmaceutically-acceptable salts thereof, may be used on their own orin the form of appropriate medicinal preparations for enteral orparenteral administration. According to a further aspect of theinvention, there is provided a pharmaceutical composition includingpreferably less than 80% and more preferably less than 50% by weight ofa compound of the invention in admixture with an inertpharmaceutically-acceptable diluent or carrier.

Examples of diluents and carriers are:

for tablets and dragees: lactose, starch, talc, stearic acid;

for capsules: tartaric acid or lactose;

for injectable solutions: water, alcohols, glycerin, vegetable oils;

for suppositories: natural or hardened oils or waxes.

There is also provided a process for the preparation of such apharmaceutical composition which comprises mixing the ingredients.

Utility

A further aspect of the invention is the use of a compound according tothe invention, an enantiomer thereof or a pharmaceutically-acceptablesalt thereof, in the manufacture of a medicament for the treatment orprophylaxis of one of the below mentioned diseases or conditions; and amethod of treatment or prophylaxis of one of the above mentioneddiseases or conditions, which comprises administering a therapeuticallyeffective amount of a compound according to the invention, or anenantiomer thereof or a pharmaceutically-acceptable salt thereof, to apatient.

Compounds according to the invention are agonists of nicotinicacetylcholine receptors. While not being limited by theory, it isbelieved that agonists of the α₇ nAChR (nicotinic acetylcholinereceptor) subtype should be useful in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders, and haveadvantages over compounds which are or are also agonists of the α₄ nAChRsubtype. Therefore, compounds which are selective for the α₇ nAChRsubtype are preferred. The compounds of the invention are indicated aspharmaceuticals, in particular in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders. Examples ofpsychotic disorders include schizophrenia, mania and manic depression,and anxiety. Examples of intellectual impairment disorders includeAlzheimer's disease, learning deficit, cognition deficit, attentiondeficit, Lewy Body Dementia, memory loss, and Attention DeficitHyperactivity Disorder. The compounds of the invention may also beuseful as analgesics in the treatment of pain (including chronic pain)and in the treatment or prophylaxis of Parkinson's disease, Huntington'sdisease, Tourette's syndrome, and neurodegenerative disorders in whichthere is loss of cholinergic synapses. The compounds may further beindicated for the treatment or prophylaxis of jetlag, for use ininducing the cessation of smoking, and for the treatment or prophylaxisof nicotine addiction (including that resulting from exposure toproducts containing nicotine).

It is also believed that compounds according to the invention are usefulin the treatment and prophylaxis of ulcerative colitis.

Pharmacology

The pharmacological activity of the compounds of the invention may bemeasured in the tests set out below:

Test A—Assay for Affinity at α₇ nAChR Subtype

₁₂₅I-α-Bungarotoxin (BTX) binding to rat hippocampal membranes. Rathippocampi were homogenized in 20 volumes of cold homogenisation buffer(HB: concentrations of constituents (mM):tris(hydroxymethyl)aminomethane 50; MgCl₂ 1; NaCl 120; KCl 5: pH 7.4).The homogenate was centrifuged for 5 minutes at 1000 g, the supernatantwas saved and the pellet re-extracted. The pooled supernatants werecentrifuged for 20 minutes at 12000 g, washed, and re-suspended in HB.Membranes (30-80 μg) were incubated with 5 nM [₁₂₅I] α-BTX, 1 mg/mL BSA(bovine serum albumin), test drug, and either 2 mM CaCl₂ or 0.5 mM EGTA[ethylene glycol-bis(β-aminoethylether)] for 2 hours at 21° C., and thenfiltered and washed 4 times over Whatman glass fibre filters (thicknessC) using a Brandel cell harvester. Pre-treating the filters for 3 hourswith 1% (BSA/0.01% PEI (polyethyleneimine) in water was critical for lowfilter blanks (0.07% of total counts per minute). Non-specific bindingwas described by 100 μM (−)-nicotine, and specific binding was typically75%.

Test B—Assay for Affinity to the α₄ nAChR Subtype

[₃H]-(−)-nicotine binding. Using a procedure modified fromMartino-Barrows and Kellar (Mol Pharm (1987) 31:169-174), rat brain(cortex and hippocampus) was homogenised as in the [₁₂₅I] α-BTX bindingassay, centrifuged for 20 minutes at 12,000×g, washed twice, and thenre-suspended in HB containing 100 μM diisopropyl fluorophosphate. After20 minutes at 4° C., membranes (approximately 0.5 mg) were incubatedwith 3 nM [3H]-(−)-nicotine, test drug, 1 μM atropine, and either 2 mMCaCl₂ or 0.5 mM EGTA for 1 hour at 4° C., and then filtered over Whatmanglass fibre filters (thickness C) (pre-treated for 1 hour with 0.5% PEI)using a Brandel cell harvester. Non-specific binding was described by100 μM carbachol, and specific binding was typically 84%.

Binding Data Analysis for Tests A and B

IC₅₀ values and pseudo Hill coefficients (n_(H)) were calculated usingthe non-linear curve fitting program ALLFIT (DeLean A, Munson P J andRodbard D (1977) Am. J. Physiol., 235:E97-E102). Saturation curves werefitted to a one site model, using the non-linear regression programENZFITTER (Leatherbarrow, R. J. (1987)), yielding K_(D) values of 1.67and 1.70 nM for the ₁₂₅I-α-BTX and [₃H]-(−)-nicotine ligandsrespectively. K_(i) values were estimated using the generalCheng-Prusoff equation:K _(i) =[IC ₅₀]/((2+([ligand]/K _(D)])^(n))^(1/n)−1)where a value of n=1 was used whenever n_(H)<1.5 and a value of n=2 wasused when n_(H)≧1.5. Samples were assayed in triplicate and weretypically ±5%. K_(i) values were determined using 6 or more drugconcentrations. The compounds of the invention are compounds withbinding affinities (K_(i)) of less than 10 μM in either Test A or TestB, indicating that they are expected to have useful therapeuticactivity.

The compounds of the invention have the advantage that they may be lesstoxic, be more efficacious, be longer acting, have a broader range ofactivity, be more potent, produce fewer side effects, are more easilyabsorbed or have other useful pharmacological properties.

General Experimental Procedures

Commercial reagents were used without further purification. Mass spectrawere recorded using either a Hewlett Packard 5988A or a MicroMassQuattro-1 Mass Spectrometer and are reported as m/z for the parentmolecular ion. Room temperature refers to 20-25° C.

EXAMPLES

The following examples are preferred non-limiting examples embodyingpreferred aspects of the invention.

Intermediate 1(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide)

A mixture of (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride (655mg), 5-bromofuran-2-carboxylic acid (681 mg), 1-hydroxybenzotriazolehydrate (457 mg), O-benzotriazol-1-yl-N,N,N′-tetramethyluroniumtetrafluoroborate (1.069 g), and N,N-diisopropylethylamine (2.5 mL) inN,N-dimethylformamide (10 mL) was agitated until a homogenous solutionwas obtained, and was then allowed to stand at room temperatureovernight. The solution was evaporated, and the residue was partitionedbetween aqueous sodium hydroxide and chloroform. The chloroform layerwas dried over magnesium sulfate, filtered, and evaporated and theresidue was purified by chromatography on silica gel in a solid phaseextraction cartridge using ammoniated methanol/chloroform mixtures asthe eluent. The compound was then dissolved in tetrahydrofuran (20 mL),excess hydrogen chloride (5 mL; 1M solution in diethyl ether) was added,and the solution was evaporated and then recrystallised frommethanol/diethyl ether to give the hydrochloride salt of the titlecompound as a colourless solid (538 mg); MS (ES⁺) 299, 301 (MH⁺).

Intermediate 2(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide)

A mixture of (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride (4 g),5-bromothiophene-2-carboxylic acid (4.25 g), 1-hydroxybenzotriazolehydrate (2.77 g), O-benzotriazol-1-yl-N,N,N′-tetramethyluroniumtetrafluoroborate (6.6 g), and N,N-diisopropylethylamine (14 mL), inN,N-dimethylformamide (100 mL) was stirred at room temperatureovernight. The solution was evaporated, and the residue was partitionedbetween aqueous sodium hydroxide and chloroform. The chloroform layerwas dried over magnesium sulfate, filtered, and evaporated. The residuewas purified by flash chromatography on silica gel and eluted with5%-20% 3.5N methanolic ammonia/chloroform mixtures. Evaporation ofsolvent gave yellow solid (5.87 g); MS (ES⁺) 315, 317 (MH⁺).

Intermediate 3(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide)

A mixture of (S)-N-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride (1.9g), 5-bromothiophene-2-carboxylic acid (1.97 g), 1-hydroxybenzotriazolehydrate (1.28 g), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (3.06 g), and N,N-diisopropylethylamine (8.3 mL) inN,N-dimethylformamide (20 mL) was stirred at room temperature overnight.The solution was evaporated, and the residue was partitioned betweenaqueous sodium hydroxide and chloroform. The chloroform layer was dried(Mg₂SO₄), filtered, and evaporated. The residue was purified by flashchromatography on silica gel and eluted with 5%-20% 3.5M methanolicammonia/chloroform mixtures. Evaporation of solvent gave white solid (3g); MS (ES⁺) 315, 317 (MH⁺).

Intermediate 4 (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide)

Prepared by a method analogous to that described for the preparation ofIntermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochlorideand 3-bromobenzoic acid; the compound was purified by chromatography onsilica gel using ammoniated methanol/chloroform mixtures as the eluent.The compound was then dissolved in tetrahydrofuran, excess hydrogenchloride (1M solution in diethyl ether) was added, and the solution wasevaporated and then recrystallised from methanol/diethyl ether to givethe hydrochloride salt of the title compound as a colourless solid; MS(ES⁺) 309, 311 (MH⁺).

Intermediate 5 (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-bromobenzamide)

Prepared by a method analogous to that described for the preparation ofIntermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochlorideand 4-bromobenzoic acid; the compound was purified by chromatography onsilica gel using ammoniated methanol/chloroform mixtures as the eluent.The compound was then dissolved in tetrahydrofuran, excess hydrogenchloride (1M solution in diethyl ether) was added, and the solution wasevaporated and then recrystallised from methanol/t-butyl methyl ether togive the hydrochloride salt of the title compound as a colourless solid;MS (ES⁺) 309, 311 (MH⁺).

Intermediate 6 (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-iodobenzamide)

Prepared by a method analogous to that described for the preparation ofIntermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochlorideand 3-iodobenzoic acid; the compound was purified by solid phaseextraction on silica gel using ammoniated methanol/chloroform mixturesas the eluent followed by reverse phase HPLC on a Waters Bondapak® C₁₈column using a gradient of acetonitrile and 0.1% aqueous trifluoroaceticacid as the eluent. The product-containing fractions were evaporated,the residue was dissolved in methanol, excess hydrogen chloride solution(4M in 1,4-dioxane) was added and the solution was evaporated to givethe hydrochloride salt of the title compound as a colourless solid; MS(ES⁺) 357 (MH⁺).

Intermediate 7 (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-iodobenzamide)

Prepared by a method analogous to that described for the preparation ofIntermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochlorideand 4-iodobenzoic acid; the compound was purified by solid phaseextraction on silica gel using ammoniated methanol/chloroform mixturesas the eluent followed by reverse phase HPLC on a Waters Bondapak® C₁₈column using a gradient of acetonitrile and 0.1% aqueous trifluoroaceticacid as the eluent. The product-containing fractions were evaporated,the residue was dissolved in methanol, excess hydrogen chloride solution(4M in 1,4-dioxane) was added and the solution was evaporated to givethe hydrochloride salt of the title compound as a colourless solid; MS(ES⁺) 357 (MH⁺).

Intermediate 8(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-bromothiophene-2-carboxamide)

(A) 4-Bromothiophene-2-carboxylic acid

Chromium(VI) oxide (20 g), and concentrated sulfuric acid (32 g) weredissolved in water (50 mL) and when dissolution was complete, the volumewas made up to 100 mL with water. 55 mL of the resulting solution wasadded dropwise to a solution of 4-bromothiophene-2-carboxaldehyde (19.1g) in acetone (200 mL) stirred at 0° C. After 2 h, the solution wasdiluted with water and extracted with chloroform. The organic extractswere washed with water, then extracted with aqueous sodium hydroxide.The alkaline mixture was acidified by cautious addition of concentratedhydrochloric acid then extracted with chloroform. The organic layer wasthen dried(Mg₂SO₄), filtered, and evaporated. The resulting solid wasrecrystallised from diethyl ether/hexane to give a colourless solid; MS(ES⁺) 207, 209 (MH⁺).

(B) (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-bromothiophene-2-carboxamide)

Prepared by a method analogous to that described for the preparation ofIntermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochlorideand 4-bromothiophene-2-carboxylic acid. The residue from evaporation ofthe reaction mixture was partitioned between aqueous hydrochloric acidand chloroform. The aqueous layer was then basified with aqueous sodiumhydroxide and extracted with chloroform. The organic extracts were dried(MgSO₄), filtered, and evaporated and resulting solid was recrystallisedfrom ethyl acetate/hexane to give the title compound as a colourlesssolid; MS (ES⁺) 315, 317 (MH⁺).

Intermediate 9(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-3-carboxamide)

(A) 5-Bromothiophene-3-carboxylic acid

Bromine (46.5 g) in acetic acid (200 mL) was added dropwise to asolution of thiophene-3-carboxylic acid (38 g) in acetic acid (300 mL).After the addition was complete, stirring was continued at roomtemperature for 30 min. The reaction mixture was poured into 2000 mL ofice/water and the precipitated solid was collected and recrystallisedfrom water to give a colourless solid; MS (ES⁻) 205, 207 (MH⁺).

(B) (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-3-carboxamide)

Prepared by a method analogous to that described for the preparation ofIntermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochlorideand 5-bromothiophene-3-carboxylic acid. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. Theproduct-containing fractions were evaporated, the residues dissolved inmethanol, excess hydrogen chloride solution (4M in 1,4-dioxane) wasadded and the solution was evaporated. After drying under vacuum, thehydrochloride salt of the title compound was obtained as a colourlesssolid; MS (ES⁺) 315, 317 (MH⁺).

Example 1(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylfuran-2-carboxamide)

(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide)hydrochloride(100 mg), phenylboronic acid (45 mg),tetrakis(triphenylphosphine)palladium(0) (20 mg), cesium carbonate (547mg), in a mixture of 1,2-dimethoxyethane (6 mL), ethanol (1.5 mL) andwater (1 mL) were stirred under reflux under a nitrogen atmosphere for17 h. The solution was evaporated and the residue was dissolved inchloroform. The solution was washed with aqueous sodium carbonate andthe organic layer was then dried (Mg₂SO₄), filtered, and evaporated.HPLC purification using a gradient of 1:1 ammoniated methanol inchloroform, and chloroform gave the title compound as a colourless solid(63 mg); MS (ES⁺) 297 (MH⁺).

Example 2(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and3-fluorobenzeneboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byfiltration through a silica gel solid phase extraction cartridge usingammoniated methanol/chloroform mixtures as the eluent, and then byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of solvent gave the trifluoroacetate salt of the titlecompound as a colourless solid; MS (ES⁺) 315 (MH⁺).

Example 3 (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-thienyl)benzamide)

Prepared by a method analogous to that described in Example 1 from(R)-1-azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide) and3-thiopheneboronic acid, using tetrakis(triphenylphosphine)palladium(0)and sodium carbonate in a mixture of tetrahydrofuran, ethanol, andwater. The compound was purified by reverse phase HPLC on a WatersBondapak® C₁₈ column using a gradient of acetonitrile and 0.1% aqueoustrifluoroacetic acid as the eluent. Evaporation of solvent gave thetrifluoroacetate of the title compound as a colourless solid; MS (ES⁺)313 (MH⁺).

Example 4 (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-phenylbenzamide)

Prepared by a method analogous to that described in Example 1 from(R)-1-azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide) and phenylboronicacid, using tetrakis(triphenylphosphine)palladium(0) and sodiumcarbonate in a mixture of tetrahydrofuran, ethanol, and water. Thecompound was purified by flash chromatography on silica gel and elutedwith 3%-10% 3.5N methanolic ammonia/chloroform mixtures. Evaporation ofsolvent gave the title compound as a colourless solid; MS (ES⁺) 307(MH⁺).

Example 5 (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-pyridyl)benzamide)

Prepared by a method analogous to that described in Example 1 from(R)-1-azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide) andpyridine-3-boronic acid, using tetrakis(triphenylphosphine)palladium(0)and sodium carbonate in a mixture of tetrahydrofuran, ethanol, andwater. The compound was purified by reverse phase HPLC on a WatersBondapak® C₁₈ column using a gradient of acetonitrile and 0.1% aqueoustrifluoroacetic acid as the eluent. The product-containing fractionswere then evaporated and the residue dissolved in methanol. Excesshydrogen chloride solution (1M in diethyl ether) was added and thesolution was evaporated. After drying under vacuum, the dihydrochloridesalt of the title compound was obtained as a colourless solid; MS (ES⁺)308 (MH⁺).

Example 6(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) andphenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) andsodium carbonate in a mixture of tetrahydrofuran, ethanol, and water.The compound was purified by reverse phase HPLC on a Waters Bondapak®C₁₈ column using a gradient of acetonitrile and 0.1% aqueoustrifluoroacetic acid as the eluent. Evaporation of theproduct-containing fractions gave the trifluoroacetate salt of the titlecompound as a colourless solid; MS (ES⁺) 313 (MH⁺).

Example 7(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-methoxyphenyl)benzamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide) and3-methoxyphenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and cesium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 337 (MH⁺).

Example 8(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(2-methoxyphenyl)benzamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide) and2-methoxyphenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and cesium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 337 (MH⁺).

Example 9(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-(N-acetylamino)phenyl)benzamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide) and3-(N-acetylamino)phenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and cesium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 364 (MH⁺).

Example 10(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-fluorophenyl)benzamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide) and3-fluorobenzeneboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and cesium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 325 (MH⁺).

Example 11(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3-methylphenyl)benzamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide) and3-methylphenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and cesium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 321 (MH⁺).

Example 12 (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(2-thienyl)benzamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide) and2-thiopheneboronic acid, using tetrakis(triphenylphosphine)palladium(0),cesium carbonate in a mixture of 1,2-dimethoxyethane and water. Thecompound was purified by reverse phase HPLC on a Waters Bondapak® C₁₈column using a gradient of acetonitrile and 0.1% aqueous trifluoroaceticacid as the eluent. Evaporation of the product-containing fractions gavethe trifluoroacetate salt of the title compound as a colourless solid;MS (ES⁺) (MH⁺).

Example 13(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(3,5-dichlorophenyl)benzamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide) and3,5-dichlorophenylboronic acid,tetrakis(triphenylphosphine)palladium(0), cesium carbonate in a mixtureof 1,2-dimethoxyethane and water. The compound was purified by reversephase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 375,377 MH⁺).

Example 14 (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(2-naphthyl)benzamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide) and2-naphthaleneboronic acid, tetrakis(triphenylphosphine)palladium(0),cesium carbonate in a mixture of 1,2-dimethoxyethane and water. Thecompound was purified by reverse phase HPLC on a Waters Bondapak® C₁₈column using a gradient of acetonitrile and 0.1% aqueous trifluoroaceticacid as the eluent. Evaporation of the product-containing fractions gavethe trifluoroacetate salt of the title compound as a colourless solid;MS (ES⁺) 357 (MH⁺).

Example 15(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(3-(4-fluorophenyl)benzamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide) and4-fluorophenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and cesium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 325 (MH⁺).

Example 16(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) andpyridine-3-boronic acid, using tetrakis(triphenylphosphine)palladium(0)and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water.The compound was purified by reverse phase HPLC on a Waters Bondapak®C₁₈ column using a gradient of acetonitrile and 0.1% aqueoustrifluoroacetic acid as the eluent. The product-containing fractionswere then evaporated and the residue dissolved in methanol. Excesshydrogen chloride solution (1M in diethyl ether) was added and thesolution was evaporated. After drying under vacuum, the dihydrochloridesalt of the title compound was obtained as a colourless solid; MS (ES⁺)298 (MH⁺).

Example 17(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-thienyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and3-thiopheneboronic acid, tetrakis(triphenylphosphine)palladium(0),sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. Thecompound was purified by reverse phase HPLC on a Waters Bondapak® C₁₈column using a gradient of acetonitrile and 0.1% aqueous trifluoroaceticacid as the eluent. Evaporation of the product-containing fractions gavethe trifluoroacetate salt of the title compound as a colourless solid;MS (ES⁺) 303 (MH⁺).

Example 18(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-benzo[b]furanyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) andbenzo[b]furan-2-boronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of tetrahydrofuran, ethanol and water. The compound was purifiedby reverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradientof acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 337 (MH⁺).

Example 19(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) andpyridine-4-boronic acid, using tetrakis(triphenylphosphine)palladium(0)and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. Thecompound was purified by reverse phase HPLC on a Waters Bondapak® C₁₈column using a gradient of acetonitrile and 0.1% aqueous trifluoroaceticacid as the eluent. The product-containing fractions were thenevaporated and the residue dissolved in methanol. Excess hydrogenchloride solution (1M in diethyl ether) was added and the solution wasevaporated. After drying under vacuum, the dihydrochloride salt of thetitle compound was obtained as a colourless solid; MS (ES⁺) 298 (MH⁺).

Example 20(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-thienyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and2-thiopheneboronic acid, using tetrakis(triphenylphosphine)palladium(0)and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water.The compound was purified by reverse phase HPLC on a Waters Bondapak®C₁₈ column using a gradient of acetonitrile and 0.1% aqueoustrifluoroacetic acid as the eluent. Evaporation of theproduct-containing fractions gave the trifluoroacetate salt of the titlecompound as a colourless solid; MS (ES⁺) 303 (MH⁺).

Example 21(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and3-methoxyphenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of tetrahydrofuran, ethanol and water. The compound was purifiedby reverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradientof acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 327 (MH⁺).

Example 22(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-methoxyphenyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and2-methoxyphenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of tetrahydrofuran, ethanol and water. The compound was purifiedby reverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradientof acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 327 (MH⁺).

Example 23(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-fluorophenyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and4-fluorophenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of tetrahydrofuran, ethanol and water. The compound was purifiedby reverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradientof acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 315 (MH⁺).

Example 24(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-naphthyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and2-naphthaleneboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and cesium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 347 (MH⁺).

Example 25(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-methylphenyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and3-methylphenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and cesium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 311 (MH⁺).

Example 26(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-furyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and3-furanboronic acid, using tetrakis(triphenylphosphine)palladium(0) andcesium carbonate in a mixture of 1,2-dimethoxyethane and water. Thecompound was purified by reverse phase HPLC on a Waters Bondapak® C₁₈column using a gradient of acetonitrile and 0.1% aqueous trifluoroaceticacid as the eluent. Evaporation of the product-containing fractions gavethe trifluoroacetate salt of the title compound as a colourless solid;MS (ES⁺) 287 (MH⁺).

Example 27(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-furyl)furan-2-carboxamide)

A mixture of(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) (146mg), 2-(tri-n-butylstannyl)furan (0.15 mL),tris(dibenzylideneacetone)dipalladium(0) (13 mg), lithium chloride (59mg), and tri(o-tolyl)phosphine (44 mg) in 1,2-dimethoxyethane (2 mL) wasstirred under reflux under a nitrogen atmosphere for 5 h. The solutionwas filtered and evaporated. The compound was purified by filtrationthrough a silica gel solid phase extraction cartridge using ammoniatedmethanol/chloroform mixtures as the eluent, and then by reverse phaseHPLC on a Waters Bondapak® C₁₈ column using a gradient of acetonitrileand 0.1% aqueous trifluoroacetic acid as the eluent. Evaporation of theproduct-containing fractions gave the trifluoroacetate salt of the titlecompound as a colourless solid (59 mg); MS (ES⁺) 287 (MH⁺).

Example 28(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 27 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and2-(tri-n-butylstannyl)pyridine. The compound was purified by filtrationthrough a silica gel solid phase extraction cartridge using ammoniatedmethanol/chloroform mixtures as the eluent, and then by reverse phaseHPLC on a Waters Bondapak® C₁₈ column using a gradient of acetonitrileand 0.1% aqueous trifluoroacetic acid as the eluent. Theproduct-containing fractions were then evaporated and the residuedissolved in methanol. Excess hydrogen chloride solution (1M in diethylether) was added and the solution was evaporated. After drying undervacuum, the dihydrochloride salt of the title compound was obtained as alight yellow solid; MS (ES⁺) 298 (MH⁺).

Example 29(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) andpyridine-4-boronic acid, using tetrakis(triphenylphosphine)palladium(0)and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water.The compound was purified by reverse phase HPLC on a Waters Bondapak®C₁₈ column using a gradient of acetonitrile and 0.1% aqueoustrifluoroacetic acid as the eluent. The product-containing fractionswere then evaporated and the residue dissolved in methanol. Excesshydrogen chloride solution (1M in diethyl ether) was added and thesolution was evaporated. Recrystallisation from methanol/diethyl ethergave the dihydrochloride salt of the title compound as a colourlesssolid; MS (ES⁺) 314 (MH⁺).

Example 30(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) andpyridine-3-boronic acid, using tetrakis(triphenylphosphine)palladium(0)and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water.The compound was purified by reverse phase HPLC on a Waters Bondapak®C₁₈ column using a gradient of acetonitrile and 0.1% aqueoustrifluoroacetic acid as the eluent. The product-containing fractionswere then evaporated and the residue dissolved in methanol. Excesshydrogen chloride solution (1M in diethyl ether) was added and thesolution was evaporated. Recrystallisation from methanol/diethyl ethergave the dihydrochloride salt of the title compound as a colourlesssolid; MS (ES⁺) 314 (MH⁺).

Example 31(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 27 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and2-(tri-n-butylstannyl)pyridine. The compound was purified by filtrationthrough a silica gel solid phase extraction cartridge using ammoniatedmethanol/chloroform mixtures as the eluent, and then by reverse phaseHPLC on a Waters Bondapak® C₁₈ column using a gradient of acetonitrileand 0.1% aqueous trifluoroacetic acid as the eluent. Theproduct-containing fractions were then evaporated and the residuedissolved in methanol. Excess hydrogen chloride solution (1M in diethylether) was added and the solution was evaporated. Recrystallisation frommethanol/diethyl ether gave the dihydrochloride salt of the titlecompound as a light yellow solid; MS (ES⁺) 314 (MH⁺).

Example 32(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-(2-pyridyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 27 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(4-bromothiophene-2-carboxamide) and2-(tri-n-butylstannyl)pyridine. The compound was purified by filtrationthrough a silica gel solid phase extraction cartridge using ammoniatedmethanol/chloroform mixtures as the eluent, and then by reverse phaseHPLC on a Waters Bondapak® C₁₈ column using a gradient of acetonitrileand 0.1% aqueous trifluoroacetic acid as the eluent. Theproduct-containing fractions were then evaporated and the residuedissolved in methanol. Excess hydrogen chloride solution (1M in diethylether) was added and the solution was evaporated. After drying undervacuum, the dihydrochloride salt of the title compound was obtained as alight yellow solid; MS (ES⁺) 314 (MH⁺).

Example 33(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-(4-pyridyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(4-bromothiophene-2-carboxamide) andpyridine-4-boronic acid, using tetrakis(triphenylphosphine)palladium(0)and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water.The compound was purified by reverse phase HPLC on a Waters Bondapak®C₁₈ column using a gradient of acetonitrile and 0.1% aqueoustrifluoroacetic acid as the eluent. The product-containing fractionswere then evaporated and the residue dissolved in methanol. Excesshydrogen chloride solution (1M in diethyl ether) was added and thesolution was evaporated. After drying under vacuum, the dihydrochloridesalt of the title compound was obtained as a colourless solid; MS (ES⁺)314 (MH⁺).

Example 34(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-(3-pyridyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(4-bromothiophene-2-carboxamide) andpyridine-3-boronic acid, using tetrakis(triphenylphosphine)palladium(0)and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water.The compound was purified by reverse phase HPLC on a Waters Bondapak®C₁₈ column using a gradient of acetonitrile and 0.1% aqueoustrifluoroacetic acid as the eluent. The product-containing fractionswere then evaporated and the residue dissolved in methanol. Excesshydrogen chloride solution (1M in diethyl ether) was added and thesolution was evaporated. Recrystallisation from methanol/diethyl ethergave the dihydrochloride salt of the title compound as a colourlesssolid; MS (ES⁺) 314 (MH⁺).

Example 35(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and3-(N-acetylamino)phenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. Theproduct-containing fractions were then evaporated and the residuedissolved in methanol. Excess hydrogen chloride solution (1M in diethylether) was added and the solution was evaporated. Recrystallisation frommethanol/diethyl ether gave the hydrochloride salt of the title compoundas a yellow solid; MS (ES⁺) 354 (MH⁺).

Example 36(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-nitrophenyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and3-nitrophenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of ethylene glycol dimethyl ether and water. The compound waspurified by reverse phase HPLC on a Waters Bondapak® C₁₈ column using agradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as theeluent. The product-containing fractions were then evaporated and theresidue dissolved in methanol. Excess hydrogen chloride solution (1M indiethyl ether) was added and the solution was evaporated.Recrystallisation from methanol/diethyl ether gave the hydrochloridesalt of the title compound as a yellow solid; MS (ES⁺) 342 (MH⁺).

Example 37(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-trifluoromethylphenylfuran-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and3-trifluoromethylphenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. Theproduct-containing fractions were then evaporated and the residuedissolved in methanol. Excess hydrogen chloride solution (1M in diethylether) was added and the solution was evaporated. After drying undervacuum, the hydrochloride salt of the title compound was obtained as acolourless solid; MS (ES⁺) 365 (MH⁺).

Example 38(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and3-chlorophenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. Theproduct-containing fractions were then evaporated and the residuedissolved in methanol. Excess hydrogen chloride solution (1M in diethylether) was added and the solution was evaporated. After drying undervacuum, the hydrochloride salt of the title compound was obtained as acolourless solid; MS (ES⁺) 331 (MH⁺).

Example 39(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and3-(N-acetylamino)phenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 370 (MH⁺).

Example 40(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and3-fluorophenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 331 (MH⁺).

Example 41(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and3-methoxyphenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent.Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 343 (MH⁺).

Example 42(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-ethoxyphenyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and3-ethoxyphenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of tetrahydrofuran, ethanol, and water. The compound waspurified by reverse phase HPLC on a Waters Bondapak® C₁₈ column using agradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as theeluent. Evaporation of the product-containing fractions gave thetrifluoroacetate salt of the title compound as a colourless solid; MS(ES⁺) 357 (MH⁺).

Example 43(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and 3,5dimethylisoxazolyl-4-boronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. Theproduct-containing fractions were then evaporated and the residuedissolved in methanol. Excess hydrogen chloride solution (1M in diethylether) was added and the solution was evaporated. Recrystallisation frommethanol/diethyl ether gave the hydrochloride salt of the title compoundas a colourless solid; MS (ES⁺) 316 (MH⁺).

Example 44(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and3,5-dimethylisoxazolyl-4-boronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. Theproduct-containing fractions were then evaporated and the residuedissolved in methanol. Excess hydrogen chloride solution (1M in diethylether) was added and the solution was evaporated. Recrystallisation frommethanol/diethyl ether gave the hydrochloride salt of the title compoundas a colourless solid; MS (ES⁺) 332 (MH⁺).

Example 45(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and3-aminophenylboronic acid hydrochloride, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of 1,2-dimethoxyethane and water. The compound was purified byreverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradient ofacetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. Theproduct-containing fractions were then evaporated and the residuedissolved in methanol. Excess hydrogen chloride solution (1M in diethylether) was added and the solution was evaporated. Recrystallisation frommethanol/diethyl ether gave the dihydrochloride salt of the titlecompound as a colourless solid; MS (ES⁺) 328 (MH⁺).

Example 46(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-3-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-3-carboxamide) andpyridine-3-boronic acid, using tetrakis(triphenylphosphine)palladium(0),and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. Thecompound was purified by reverse phase HPLC on a Waters Bondapak® C₁₈column using a gradient of acetonitrile and 0.1% aqueous trifluoroaceticacid as the eluent. The product-containing fractions were thenevaporated and the residue dissolved in methanol. Excess hydrogenchloride solution (1M in diethyl ether) was added and the solution wasevaporated. Recrystallisation from methanol/diethyl ether gave thedihydrochloride salt of the title compound as a colourless solid; MS(ES⁺) 314 (MH⁺).

Example 47(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-chlorophenyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and5-(4-chlorophenyl)furoic acid; the compound was purified bychromatography on silica gel using ammoniated methanol/chloroformmixtures as the eluent; MS (ES⁺) 331, 333 (MH⁺).

Example 48(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(2-(3-pyridyl)thiazole-4-carboxamide)

A mixture of (R)-N-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride (294mg), 2-(3-pyridyl)thiazole-4-carboxylic acid (304 mg),1-hydroxybenzotriazole hydrate (199 mg),O-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (473g), and N,N-diisopropylethylamine (1.0 mL) in N,N-dimethylformamide (10mL) was stirred at room temperature overnight. The solution wasevaporated, and the residue was partitioned between aqueous sodiumhydroxide and chloroform. The solution was evaporated and the residuewas purified by reverse phase HPLC on a Waters Bondapak® C₁₈ columnusing a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acidas the eluent. The hydrochloride salt was prepared by evaporation of theproduct-containing fractions, dissolution of the residue in methanol,addition of excess hydrogen chloride solution (1M in diethyl ether) andevaporation. Recrystallisation from methanol/diethyl ether gave thedihydrochloride salt of the title compound as a colourless solid (428mg); MS (ES⁺) 315 (MH⁺).

Example 49(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(2-(4-pyridyl)thiazole-4-carboxamide)

A mixture of (R)-N-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride (236mg), 2-(4-pyridyl)thiazole-4-carboxylic acid (243 mg),1-hydroxybenzotriazole hydrate (159 mg),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (379mg), and N,N-diisopropylethylamine (0.82 mL) in N,N-dimethylformamide(10 mL) was stirred at room temperature overnight. The solution wasevaporated, and the residue was partitioned between aqueous sodiumhydroxide and chloroform. The solution was evaporated and the residuewas purified by reverse phase HPLC on a Waters Bondapak® C₁₈ columnusing a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acidas the eluent. The hydrochloride salt was prepared by evaporation of theproduct-containing fractions, dissolution of the residue in methanol,addition of excess hydrogen chloride solution (1M in diethyl ether) andevaporation. Recrystallisation from methanol/diethyl ether gave thedihydrochloride salt of the title compound as a colourless solid (428mg); MS (ES⁺) 315 (MH⁺).

Example 50(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N,N-dimethylamino)phenyl)thiophene-2-carboxamide)

Formaldehyde (37% solution in water, 0.18 mL) was added to a solution of(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)-thiophene-2-carboxamide)(92 mg) in 1% acetic acid in methanol (5 mL). After 30 minutes at roomtemperature, sodium cyanoborohydride (35 mg) was added, and the reactionmixture was stirred at room temperature for 1 h. The solution wasevaporated and the residue was purified by reverse phase HPLC on aWaters Bondapak® C₁₈ column using a gradient of acetonitrile and 0.1%aqueous trifluoroacetic acid as the eluent. The hydrochloride salt wasprepared by evaporation of the product-containing fractions, dissolutionof the residue in methanol, addition of excess hydrogen chloridesolution (1M in diethyl ether) and evaporation. Recrystallisation frommethanol/diethyl ether gave the dihydrochloride salt of the titlecompound as a colourless solid (54 mg); MS (ES⁺) 356 (MH⁺).

Example 51(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(8-quinolinyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-aza-bicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and8-quinolineboronic acid, tetrakis(triphenylphosphine)palladium(0),sodium carbonate in a mixture of DME, and water. The compound waspurified by reverse phase HPLC on a Waters Bondapak® C₁₈ column using agradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as theeluent. The hydrochloride salt was prepared by evaporation of theproduct-containing fractions, dissolution of the residue in methanol,addition of excess hydrogen chloride solution (1M in diethyl ether) andevaporation. Recrystallisation from methanol/diethyl ether gave thedihydrochloride salt of the title compound as a colourless solid; MS(ES⁺) 364 (MH⁺).

Example 52(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(S)-N-(1-aza-bicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) andpyridine-3-boronic acid, using tetrakis(triphenylphosphine)palladium(0)and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water.The compound was purified by reverse phase HPLC on a Waters Bondapak®C₁₈ column using a gradient of acetonitrile and 0.1% aqueoustrifluoroacetic acid as the eluent. The hydrochloride salt was preparedby evaporation of the product-containing fractions, dissolution of theresidue in methanol, addition of excess hydrogen chloride solution (1Min diethyl ether) and evaporation. Recrystallisation frommethanol/diethyl ether gave the dihydrochloride salt of the titlecompound as a colourless solid; MS (ES⁺) 314 (MH⁺).

Example 53(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) andpyridine-4-boronic acid, using tetrakis(triphenylphosphine)palladium(0)and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. Thecompound was purified by reverse phase HPLC on a Waters Bondapak® C₁₈column using a gradient of acetonitrile and 0.1% aqueous trifluoroaceticacid as the eluent. The hydrochloride salt was prepared by evaporationof the product-containing fractions, dissolution of the residue inmethanol, addition of excess hydrogen chloride solution (1M in diethylether) and evaporation. Recrystallisation from methanol/diethyl ethergave the dihydrochloride salt of the title compound as a colourlesssolid; MS (ES⁺) 314 (MH⁺).

Example 54(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 27 from(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and2-(tri-n-butylstannyl)pyridine. The compound was purified by flashchromatography 5%-20% 3.5N ammoniated methanol/chloroform mixture aseluent. The hydrochloride salt was prepared by evaporation of theproduct-containing fractions, dissolution of the residue in methanol,addition of excess hydrogen chloride solution (1M in diethyl ether) andevaporation. Recrystallisation from methanol/diethyl ether gave thedihydrochloride salt of the title compound as a colourless solid; MS(ES⁺) 314 (MH⁺)

Example 55(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) andphenylboronic acid, tetrakis(triphenylphosphine)palladium(0) and sodiumcarbonate in a mixture of tetrahydrofuran, ethanol and water. Thecompound was purified by reverse phase HPLC on a Waters Bondapak® C₁₈column using a gradient of acetonitrile and 0.1% aqueous trifluoroaceticacid as the eluent. Evaporation of the product-containing fractions gavethe trifluoroacetate salt of the title compound as a colourless solid;MS (ES⁺) 313 (MH⁺).

Example 56(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-3-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-Aza-bicyclo[2.2.2]oct-3-yl)(5-bromothiophene-3-carboxamide) andphenylboronic acid, using tetrakis(triphenylphosphine)palladium(0), andsodium carbonate in a mixture of tetrahydrofuran, ethanol and water. Thecompound was purified by reverse phase HPLC on a Waters Bondapak® C₁₈column using a gradient of acetonitrile and 0.1% aqueous trifluoroaceticacid as the eluent. Evaporation of the product-containing fractions gavethe trifluoroacetate salt of the title compound as a colourless solid;MS (ES⁺) 313 (MH⁺).

Example 57(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-phenylthiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-Aza-bicyclo[2.2.2]oct-3-yl)(4-bromothiophene-2-carboxamide) andphenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) andsodium carbonate in a mixture of tetrahydrofuran, ethanol, and water.The compound was purified by reverse phase HPLC on a Waters Bondapak®C₁₈ column using a gradient of acetonitrile and 0.1% aqueoustrifluoroacetic acid as the eluent. The hydrochloride salt was preparedby evaporation of the product-containing fractions, dissolution of theresidue in methanol, addition of excess hydrogen chloride solution (1Min diethyl ether) and evaporation. Recrystallisation from ethyl acetategave the hydrochloride salt of the title compound as a colourless solid;MS (ES⁺) 313 (MH⁺).

Example 58(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-cyanophenyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and3-cyanophenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0), and sodium carbonate in amixture of tetrahydrofuran, ethanol and water. The compound was purifiedby reverse phase HPLC on a Waters Bondapak® C₁₈ column using a gradientof acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. Thehydrochloride salt was prepared by evaporation of the product-containingfractions, dissolution of the residue in methanol, addition of excesshydrogen chloride solution (1M in diethyl ether) and evaporation.Recrystallisation from methanol/diethyl ether gave the hydrochloridesalt of the title compound as a colourless solid; MS (ES⁺) 338 (MH⁺).

Example 59(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-methylamino)phenyl)thiophene-2-carboxamide)

Sodium methoxide (14 mL, 0.5M solution in methanol) was added to thesolution of(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)thiophene-2-carboxamide)(550 mg) in methanol (5 mL), then paraformaldehyde (117 mg) was added.The mixture was heated under reflux for 1 h. After cooling the reactionmixture to room temperature, sodium borohydride (175 mg) was added, andthe solution was then heated under reflux for 2 h. Aqueous potassiumhydroxide (1M, 1.4 mL) was added. Heating under reflux was resumed for 2h and the reaction mixture was then left at room temperature for 16 h.The solvent was evaporated and the residue was purified by reverse phaseHPLC on a Waters Bondapak® C₁₈ column using a gradient of acetonitrileand 0.1% aqueous trifluoroacetic acid as the eluent. The hydrochloridesalt was prepared by evaporation of the product-containing fractions,dissolution of the residue in methanol, addition of excess hydrogenchloride solution (1M in diethyl ether) and evaporation.Recrystallisation from methanol/diethyl ether gave the dihydrochloridesalt of the title compound as a colourless solid (120 mg); MS (ES⁺) 342(MH⁺).

Example 60(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-hydroxyphenyl)thiophene-2-carboxamide)

To the(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)thiophene-2-carboxamide)(900 mg), 48% aqueous hydrobromic acid (10 mL) and glacial acetic acid(10 mL) were added. After heating under reflux for 4 h, saturatedaqueous sodium carbonate and solid sodium carbonate were added to adjustto pH 10. The aqueous layer was extracted with chloroform and thecombined extracts were dried over magnesium sulfate. After filtrationand evaporation, residue was purified by flash chromatography using5%-20% 3.5M methanolic ammonia/chloroform mixtures as the eluent. Theproduct obtained was purified by reverse phase HPLC on a WatersBondapak® C₁₈ column using a gradient of acetonitrile and 0.1% aqueoustrifluoroacetic acid as the eluent. The hydrochloride salt was preparedby evaporation of the product-containing fractions, dissolution of theresidue in methanol, addition of excess hydrogen chloride solution (1Min diethyl ether) and evaporation. Recrystallisation frommethanol/diethyl ether gave the hydrochloride salt of the title compoundas a colourless solid (32 mg); MS (ES⁺) 329 (MH⁺).

Example 61(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridylamino)thiophene-2-carboxamide)

The mixture of(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) (315mg), 3-aminopyridine (188 mg), tris(dibenzylideneacetone)dipalladium(0)(46 mg), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (62 mg),and sodium t-butoxide (192 mg) in tetrahydrofuran (10 mL) was heatedunder reflux for 20 h. The mixture was filtered and the residue waspurified by flash chromatography using 5%-20% 3.5M methanolicammonia/chloroform mixtures as the eluent. The compound was purifiedfurther by reverse phase HPLC on a Waters Bondapak® C₁₈ column using agradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as theeluent. The hydrochloride salt was prepared by evaporation of theproduct-containing fractions, dissolution of the residue in methanol,addition of excess hydrogen chloride solution (1M in diethyl ether) andevaporation. Recrystallisation from methanol/diethyl ether gave thedihydrochloride salt of the title compound as a yellow solid (77 mg); MS(ES⁺) 329 (MH⁺).

Example 62(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and3-chlorophenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of tetrahydrofuran, ethanol and water. The compound was purifiedby flash chromatography using a gradient of 5%-20% 3.5M methanolicammonia/chloroform mixtures as the eluent to give the title compound asa colourless solid; MS (ES⁺) 347 (MH⁺).

Example 63(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(4-morpholinyl)phenyl)thioiphene-2-carboxamide)

A mixture of(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)thiophene-2-carboxamide)(0.98 g), morpholine (0.5 mL), tris(dibenzylideneacetone)dipalladium(0)(132 mg), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (180 mg),and sodium t-butoxide (554 mg) in tetrahydrofuran (25 mL) was heatedunder reflux for 20 hr under nitrogen. The mixture was filtered and theresidue was purified by flash chromatography using a gradient of 5%-20%3.5M methanolic ammonia/chloroform mixtures as the eluent. The mixturewas then subjected to reverse phase HPLC on a Waters Bondapak® C₁₈column using a gradient of acetonitrile and 0.1% aqueous trifluoroaceticacid as the eluent. The hydrochloride salt was prepared by evaporationof the product-containing fractions, dissolution of the residue inmethanol, addition of excess hydrogen chloride solution (1M in diethylether) and evaporation. Recrystallisation from methanol/diethyl ethergave the dihydrochloride salt of the title compound as solid (400 mg);MS (ES⁺) 398 (MH⁺).

Example 64(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(aminomethyl)phenyl)thiophene-2-carboxamide)

To the solution of(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(3-cyanophenyl)thiophene-2-carboxamide)(311 mg) in methanol and acetic acid (1:1, 10 mL) a catalytic amount of10% Pd—C was added and the mixture was hydrogenated at 50 p.s.i. for 36hr. The mixture was filtered through a pad of celite. The residue waspurified first by flash chromatography using 5-20% 3.5M methanolicammonia/chloroform mixtures as the eluent and then by reverse phase HPLCon a Waters Bondapak® C₁₈ column using a gradient of acetonitrile and0.1% aqueous trifluoroacetic acid as the eluent. The free base wasprepared by basification of the product-containing fractions andextraction into chloroform followed by evaporation to gave the titlecompound (23 mg); MS (ES⁺) 342 (MH⁺).

Example 65(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-phenoxythiophene-2-carboxamide)

To a solution of(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) (463mg) in pyridine (10 mL) phenol (158 mg), copper iodide (32 mg) andpotassium carbonate (97 mg) were added. The mixture was stirred at 125°C. for 65 h under nitrogen. Water was added and the aqueous layer wasextracted with chloroform. Following evaporation, the residue waspurified by flash chromatography using 5-20% 3.5M methanolicammonia/chloroform mixtures as the eluent and then by reverse phase HPLCon a Waters Bondapak® C₁₈ column using a gradient of acetonitrile and0.1% aqueous trifluoroacetic acid as the eluent. The free base wasprepared by basification of the product-containing fractions andextraction into chloroform followed by evaporation to gave the titlecompound (80 mg); MS (ES⁺) 329 (MH⁺).

Example 66(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)furan-2-carboxamide)

Prepared by a method analogous to that described in Example 1 from(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and3-aminophenylboronic acid, usingtetrakis(triphenylphosphine)palladium(0) and sodium carbonate in amixture of tetrahydrofuran, ethanol and water. The compound was purifiedby flash chromatography using 5-20% 3.5M methanolic ammonia/chloroformmixtures as the eluent and then by reverse phase HPLC on a WatersBondapak® C₁₈ column using a gradient of acetonitrile and 0.1% aqueoustrifluoroacetic acid as the eluent. The free base was prepared bybasification of the product-containing fractions and extraction intochloroform followed by evaporation to gave the title compound; MS (ES⁺)312 (MH⁺).

Example 67(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(N,N-dimethylamino)phenyl)furan-2-carboxamide)

To the solution of(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)furan-2-carboxamide)(220 mg) in 1% acetic acid in ethanol (10 mL) formaldehyde (0.26 mL) wasadded. After 45 min, sodium cyanoborohydride (89 mg) was added. Themixture was stirred for 4 h. Water was added and the solution wasbasified to pH>10 by adding solid sodium carbonate. The aqueous layerwas extracted chloroform and the extracts were dried over magnesiumsulfate, filtered and evaporated. The compound was purified by flashchromatography using 5-20% 3.5M methanolic ammonia/chloroform mixturesas the eluent. The hydrochloride salt was prepared by evaporation of theproduct-containing fractions, dissolution of the residue in methanol,addition of excess hydrogen chloride solution (1M in diethyl ether) andevaporation. Recrystallisation from methanol/diethyl ether gave thedihydrochloride salt of the title compound as solid (141 mg); MS (ES⁺)340 (MH⁺).

Example 68(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-formylphenyl)thiophene-2-carboxamide)

Prepared by a method analogous to that described in example 1 from(R)-N-(1-aza-bicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and3-formylphenyl boronic acid, tetrakis(triphenylphosphine)palladium(0),sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. Thecompound was purified by reverse phase HPLC on a Waters Bondapak® C₁₈column using a gradient of acetonitrile and 0.1% aqueous trifluoroaceticacid as the eluent. The free base was prepared by basification of theproduct-containing fractions. The aqueous layer was extracted bychloroform and evaporated to gave the title compound; MS (ES⁺) 341 (MH⁺)

Example 69(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-(hydroxymethyl)phenyl)thiophene-2-carboxamide)

To the solution of(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(3-formylphenyl)thiophene-2-carboxamide)(875 mg) in methanol (15 mL), sodium borohydride (97.2 mg) was added.The mixture was then stirred at room temperature for 4 h. The residuewas partitioned between water and chloroform. The extracts were driedover magnesium sulfate, filtered, and evaporated, and the residue wasthen purified by flash chromatography using 5-20% 3.5M methanolicammonia/chloroform mixtures as the eluent to give the title compound(547 mg); MS (ES⁺) 343 (MH⁺).

1. A compound selected fromN-(1-Azabicyclo[2.2.2]oct-3-yl)(2-(3-pyridyl)thiazole-4-carboxamide), orN-(1-Azabicyclo[2.2.2]oct-3-yl)(2-(4-pyridyl)thiazole-4-carboxamide); ora pharmaceutically-acceptable salt thereof.
 2. A compound selected from(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(2-(3-pyridyl)thiazole-4-carboxamide)or(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(2-(4-pyridyl)thiazole-4-carboxamide)or a pharmaceutically-acceptable salt thereof.
 3. A compound accordingto claim 1, said compound beingN-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiazloe-2-carboxamide) ora pharmaceutically acceptable salt thereof.
 4. A compound according toclaim 2, said compound being(R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(3pyridyl)thiazole-2-carboxamide)or a pharmaceutically acceptable salt thereof.